Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes

PLoS One. 2012;7(8):e41756. doi: 10.1371/journal.pone.0041756. Epub 2012 Aug 8.


Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.

Methodology/principal findings: Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs.1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95(th) percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.

Conclusions/significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.

Trial registration: NCT00607230.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autoantibodies / chemistry
  • Autoimmunity
  • BCG Vaccine / immunology*
  • Biomarkers / metabolism
  • C-Peptide / chemistry
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / therapy*
  • Double-Blind Method
  • Female
  • Glutamate Decarboxylase / metabolism
  • Herpesvirus 4, Human / metabolism
  • Humans
  • Insulin-Secreting Cells / cytology
  • Male
  • Middle Aged
  • Placebos
  • T-Lymphocytes / cytology
  • Tumor Necrosis Factor-alpha / metabolism


  • Autoantibodies
  • BCG Vaccine
  • Biomarkers
  • C-Peptide
  • Placebos
  • Tumor Necrosis Factor-alpha
  • Glutamate Decarboxylase

Associated data